The Neural Correlates of Error-Processing in Pediatric Obsessive Compulsive Disorder

Kate Dimond Fitzgerald, M.D.

Funded in June, 2008: $200000 for 3 years

Using Brain Imaging to Understand the Developmental Basis of Obsessive-Compulsive Disorder

Investigators will use functional imaging of young patients with obsessive-compulsive disorder to ask if the brain’s error-processing circuits develop abnormally in this disorder.

Obsessive-compulsive disorder (OCD) is a common and disabling psychiatric illness characterized by intrusive, anxiety-provoking thoughts and ritualistic, repetitive behaviors. The disorder often begins in childhood or adolescence, raising the possibility that it results from atypical brain maturation. Because OCD symptoms are usually associated with the nagging sense that a mistake has been made, researchers suspect a problem in the development of the brain’s error-detecting circuitry.

One brain region in particular whose development may go awry in OCD is the rostral anterior cingulate cortex (rACC). This area is responsible for generating emotional responses to performance errors. Normally, the rACC operates in balance with more cognitive prefrontal cortical areas that are responsible for checking errors and monitoring performance. In OCD, however, the rACC appears to be hyperactive, so that emotional responses to possible errors may no longer be held in check by the brain’s prefrontal areas.

The University of Michigan investigators hypothesize that this hyperactivity of the rACC occurs because the structure develops too early or too much. The prefrontal areas that normally regulate the rACC then fail to catch up with it developmentally, resulting in a chronic imbalance between emotional and cognitive responses to error. The investigators will test this hypothesis using functional MRI (fMRI), which generates images of the activity of different brain regions while patients perform specific cognitive tasks that tend to produce errors. The investigators will perform the fMRI experiments in 48 pediatric OCD patients and 48 healthy volunteers at different developmental stages (pre-pubertal, pubertal, and adolescent), and compare rates of maturation of error-processing circuits in the two groups.

Significance: Mapping the activity of brain circuits in OCD as the disorder evolves may enable the generation of new treatment strategies tailored to specific developmental stages.

The Neural Correlates of Error-Processing in Pediatric Obsessive Compulsive Disorder

Obsessive compulsive disorder (OCD) is a common and disabling psychiatric illness, characterized by intrusive thoughts and ritualistic behaviors, that often fails to respond to currently available treatments. Although the disorder tends to emerge during childhood or adolescence, the brain abnormalities associated with pediatric OCD have not been well-studied. In adult patients, hyperactivity of the anterior cingulate cortex (ACC) has been found to occur at rest, to increase with symptom provocation and to normalize with effective treatment, but the functional significance of these findings is not well-understood.

Neuroimaging work in healthy subjects suggests that the midline prefrontal cortex (MFC)—including the ACC—mediates inhibitory and error processing along a dorsal to rostral continuum, which is especially relevant for OCD, given patients’ apparent failure to inhibit intrusive thoughts and behaviors and their excessive concern that errors have been made. Indeed, hyperactivation of the ACC in its rostral subdivision for errors, and more dorsally for correct response inhibition, has recently been demonstrated in adult OCD patients, suggesting that functional abnormalities of both inhibitory and error processing within discrete MFC subregions may exist in OCD. Because the normal mediation of inhibitory and error processing by the MFC develops dramatically during the time period in which OCD typically has its onset, mid-childhood through adolescence, it is possible that aberrant development of these functions may be associated with the emergence of OCD in youth. This possibility is consistent with the association of increased ACC volumes, symptom severity, and deficits of response inhibition in pediatric OCD patients. However, whether functional abnormalities of inhibitory and/or error-processing can be mapped to the MFC in pediatric OCD has not been directly tested.

To do so, we are conducting a functional magnetic resonance imaging (fMRI) study using the Multisource Interference Task (MSIT) to test for abnormalities of inhibitory and/or error processing within the MFC in youth with OCD. In a pilot sample of healthy children and adolescents, we have found the MSIT to yield robust activation of the dorsal MFC during correct interference and error trials, with additional activation in the rostral ACC only during errors, making it a reliable probe of this region’s function in youth. We predict that altered activation of the MFC during both inhibitory and error-processing will occur in pediatric OCD patients compared to matched healthy control subjects, and anticipate that this work will help to define the primary neurobiological correlates of the disorder.

Ultimately, the study of brain function in youngsters with who are near illness onset will contribute to the framework on which a neurodevelopmental model of OCD can be built, which, in turn, will guide the development of better treatments, and possibly even preventative strategies.

Kate Dimond Fitzgerald, M.D.

Kate Dimond Fitzgerald, M.D., is a clinical lecturer in Child and Adolescent Psychiatry at the University of Michigan. Dr. Fitzgerald completed medical school at Wayne State University School of Medicine, and then completed her residency and child fellowship training at the University of Michigan. Her clinical work is focused on the diagnosis and treatment of childhood anxiety and is complemented by her brain imaging research in pediatric obsessive compulsive disorder (OCD). Currently, she is studying how brain response to errors could interact with developmental stage to lead to obsessions and compulsions in youth. In conjunction with ongoing genetic research at the University of Michigan Child Anxiety Program, this work aims to elucidate the brain basis for pediatric OCD in order to guide the development of better treatment and preventative strategies for early onset illness.

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